The compounds of this invention exhibit V.sub.1 and/or V.sub.2 vasopressin antagonist activity without substantial agonist activity. Vasopressin is known to contribute to the antidiuretic mechanism of actions within the kidney. The action of these compounds antagonizes that of the natural anti-diuretic hormone (ADH) so as to cause the body to excrete water.
Manning et al., Nature 308, 652 (1984) has described the following compound ##STR1## as having potent vasopressin antagonist activity. Also, this compound is reported as being devoid of detectable vasopressin aqonist activity in vivo in rats. In man, however, this compound demonstrated only agonist activity (Dubb et al., Kidney Int. 31, 267 January 1987). A new test in dogs now shows that this compound does produce agonist activity.
The compounds of this invention have structures which are distinguished over the prior art in that there is a 4'-methyl substituent attached to the cyclopentamethylene propionic acid group and these compounds, while having vasopressin antagonist activity, are substantially devoid of agonist activity as shown by the test in dogs.
The effect of removal or replacement of amino acid groups in the tail of the peptide has been reported. Manning et al., Nature 308 652 (1984) and U.S. Pat. No. 4,469,679 have disclosed that the terminal glycine unit at the 9-position of certain 1 -(.beta.-mercapto .beta.,.beta.-cyclopentamethylene propionic acid) vasopressin compounds can be removed or replaced by L or D-Ala, Ser or Arg without necessarily affecting the binding at vasopressin receptors.
U.S. Pat. Nos. 4,481,194 and 4,481,193 have disclosed that removing proline at position 7 or both proline and glycine at positions 7 and 9 from the structures of vasopressin antagonist compounds will produce compounds which retain substantial, but somewhat reduced, antagonist activity.